TW201711687A - Solid dosage forms of palbociclib - Google Patents

Abstract

The present invention relates to solid dosage forms of palbociclib comprising a water-soluble acid. The dosage forms described herein have desirable pharmacokinetic characteristics.

Description

Parbsili solid dosage form

The present invention relates to 6-ethylindenyl-8-cyclopentyl-5-methyl-2-(5-piperidin a solid dosage form of 1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (P.B.), which exhibits favorable storage stability and The desired pharmacokinetic profile of the solubility properties.

Pabsili is a potent and selective inhibitor of CDK4 and CDK6, which has the following structure:

Pabsiri is described in WHO Drug Information, Vol. 27, No. 2, page 172 (2013). Pabsiri and its pharmaceutically acceptable salts are disclosed in International Publication No. WO 2003/062236 and U.S. Patent No. 6, 936, 612, 7, 208, 489 and 7, 456, 168; International Publication No. WO 2005/005426 and U.S. Patent Nos. 7,345,171 and 7,863,278; International Publication No. WO 2008/032157, and U.S. Patent No. 7,781,583; and International Publication No. WO 2014/128588. The disclosure of each of the aforementioned references is incorporated herein by reference in its entirety.

Pabsiri is approved in the United States in combination with letrozole as an initial endocrine therapy or in combination with fulvestrant for the treatment of hormone receptor (HR)-positive, human after disease progression with endocrine therapy Epidermal growth factor 2 (HER2) - negative advanced or metastatic breast cancer. The drug is marketed by Pfizer under the trade name IBRANCE® in the form of an immediate release (IR) capsule containing oral administration of paclocil as the free base.

Pabbori is a dibasic compound and has two 7.3 (second piper) A basic group of pKa of nitrogen) and 4.1 (pyridinium). The solubility of the paclitaxel free base is pH dependent. Pabsili is water soluble at low pH (2.1-4.5) and the solubility drops dramatically as the pH rises above 4.5. Pabsiri had poor water solubility (9 μg/ml) at pH 7.9. The agent that increases the pH of the stomach with administration can alter the solubility and absorption of the paclitaxel free base formulation.

When administered orally, the absorption and bioavailability of the therapeutic agent can be affected by a number of factors, including whether the subject is eating or fasting and using certain drugs, such as proton pump inhibitor (PPI) or H2 receptor antagonism. Agents, as well as certain medical symptoms. Compounds with pH-dependent solubility (especially basic compounds) can exhibit undesired pharmacokinetic properties, such as poor absorption Achieving and/or reduced bioavailability can result in significant inter-patient and patient variability.

There is still a need for an improved Pabsiri dosage form found to have a favorable dissolution and pharmacokinetic profile, and the improved dosage form also exhibits good storage stability. We have surprisingly found that the solid dosage form according to the present invention exhibits excellent storage stability and provides substantially pH-independent pabbice delivery without significant food effects or adverse interactions with PPI.

Summary of the invention

In a first aspect, the invention provides a solid dosage form comprising a paclitaxel, a water soluble acid, and a pharmaceutically acceptable carrier.

In a second aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form is added to a standard USP 2 rotating blade device having a blade of spin at 50 rpm comprising 500 at 37 °C In the test medium of 10 mM acetate buffer pH 5.5, it dissolves: (a) not less than 35% of Pabori in 15 minutes; (b) not less than 45% of Pabbo in 30 minutes Siri; (c) not less than 55% of Pabori in 60 minutes; or (d) two or more of (a), (b) and (c).

In a third aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form is added to a standard USP 2 rotary vane device having a blade of spin at 50 rpm comprising 500 at 37 °C Test of milliliter 50mM phosphate buffer pH 6.5 and 0.1M NaCl In the middle, it dissolves: (a) less than 15% of Pabori in 15 minutes; (b) less than 20% of Pabori in 30 minutes; (c) in 60 minutes In 25% of Pabbori; or (d) (a), (b) and (c) two or more.

In some embodiments, the present invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form is added to a standard USP 2 rotating blade device having a blade of spin at 50 rpm comprising 500 at 37 °C When immersed in 50 mM phosphate buffer solution of pH 6.5 and 0.1 M NaCl in the test medium, it dissolves: (a) not less than 20% of Pabori in 15 minutes; (b) not less than 30 in 30 minutes % of Pabsiri; (c) not less than 25% of Pabori in 60 minutes; or (d) two or more of (a), (b) and (c).

In other embodiments, the present invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form is added to a standard USP 2 rotating blade device having a blade of spin at 50 rpm at 37 ° C. 500 ml of 50 mM phosphate buffer of pH 6.5 and 0.1 M NaCl in the test medium, which dissolves (a) not less than 40% of Pabsiri in 15 minutes; (b) not less than 35 in 30 minutes % of Pabsiri; (c) not less than 25% of Pabori in 60 minutes; or (d) two or more of (a), (b) and (c).

In a fourth aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form: (a) the area under the plasma concentration versus time curve after administration of the subject to a single oral dose (AUC) has an average fed/fasting ratio of from about 0.8 to about 1.25; (b) an average of eating from a maximum oral plasma concentration ( _Cmax ) of from about 0.8 to about 1.25 after administration of a single oral dose to the subject. Fasting ratio; or (c) both (a) and (b).

In a fifth aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form: (a) provides an equivalent amount of Pabo after administration of a single oral dose to the subject Siri control is an average fasting AUC within the range of 80% to 125% of the average fasting AUC of immediate release (IR) oral capsules; or (b) providing equivalent after administration of a single oral dose to the subject Pabo Xi in the amount of control with immediate-release (IR) by an average of 80 to 125% of the opening of the capsule fasting average of the range of fasting plasma C _max C _max; or (c) (a) and both (b) .

In a sixth aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form: (a) is provided in a proton pump inhibitor (PPI) after administration of a single oral dose to the subject The average AUC in the presence of 80% to 125% of the mean AUC in the absence of PPI; (b) provided in the presence of a proton pump inhibitor (PPI) after administration of a single oral dose to the subject in the range of 80 to 125% of the average C _max of the mean C _max is no system in the presence of a PPI; or (c) (a) (b ) and both. In some such embodiments, the PPI is rabeprazole.

In a seventh aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form exhibits less than 0.3% by weight after storage for 96 days at 30 ° C and 75% relative humidity (RH) Acid addition.

In an eighth aspect, the present invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form exhibits less than 1.0% by weight acid adduct after storage for 2 years at 30 ° C and 75% RH .

In a ninth aspect, the invention provides a solid dosage form of any of the embodiments described herein, wherein the dosage form exhibits less than 0.05% by weight acid adduct after storage for one year at 25 ° C / 60% RH . In some such embodiments, the dosage form and the desiccant cartridge are packaged in a bottle using a heat sensitive seal.

In some embodiments of each of the aspects of the invention, the active pharmaceutical ingredient (API) Pabburry comprises from about 10% by weight to about 35% by weight of the dosage form. In a particular embodiment, the Pabsili constitutes about 20% by weight of the dosage form.

In some embodiments of each of the aspects of the invention, the water soluble acid comprises from about 5% to about 40% by weight of the dosage form. In a particular embodiment, the water soluble acid comprises from about 5% to about 25% by weight of the dosage form. In other embodiments, the water soluble acid comprises from about 5% to about 15% by weight of the dosage form. In a more particular embodiment, the water soluble acid comprises about 10% by weight of the dosage form.

In some such embodiments, the water soluble acid is selected from the group consisting of succinic acid, malic acid, and tartaric acid. In a particular embodiment, the water soluble acid is succinic acid. In other embodiments, the water soluble acid is malic acid. In another embodiment, the water soluble acid is tartaric acid.

In a preferred embodiment of each of the aspects described herein, the solid dosage form comprises from about 10% to about 35% by weight of Pabbori, from about 5% to about 25% by weight selected from the group consisting of amber Acid, malic acid and tartaric acid A group of water soluble acids and pharmaceutically acceptable carriers. In a particular embodiment, the water soluble acid is succinic acid. In some such embodiments, the solid dosage form comprises about 20% by weight of Pabsiri, about 10% by weight of succinic acid, and a pharmaceutically acceptable carrier.

In some embodiments of each of the aspects described herein, the pharmaceutically acceptable carrier comprises one or more of the following pharmaceutically acceptable excipients: diluent, disintegrant, binder , lubricants, slip agents and surfactants. Such excipients may be incorporated into the tablet form either intragranularly or extragranularly, and the lozenge may comprise the same or different excipients as either intragranular or extragranular components. For example, the lozenge formulation can comprise both the same or different intragranular lubricants, extragranular lubricants or both intragranular and extragranular lubricants.

In some embodiments of each of the aspects described herein, the pharmaceutically acceptable carrier comprises at least one diluent, wherein the diluent comprises from about 50% to about 75% by weight of the solid dosage form. In a particular embodiment, the carrier comprises at least one diluent selected from the group consisting of microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesium carbonate, hydrogen phosphate Dibasic calcium phosphate and tribasic calcium phosphate. In a particular embodiment, the diluent is microcrystalline cellulose. In some such embodiments, the diluent is microcrystalline cellulose.

In other embodiments of each of the aspects described herein, the pharmaceutically acceptable carrier comprises a lubricant, wherein the lubricant comprises from about 0.5% to about 10% by weight of the solid dosage form. In a particular embodiment, the carrier comprises at least one lubricant selected from the group consisting of stearic acid Magnesium, calcium stearate, zinc stearate and sodium stearyl fumarate. In a particular embodiment, the lubricant is magnesium stearate, which may be included in the particles, out of the particles, or both. In other embodiments, the lubricant is sodium stearyl fumarate. Other embodiments include both magnesium stearate and sodium stearyl fumarate as lubricants, which may be included in the particles, out of the particles, or both.

In a further embodiment of each of the aspects described herein, the pharmaceutically acceptable carrier comprises at least one disintegrant, wherein the disintegrant constitutes from about 5% by weight to about 10% by weight of the solid dosage form. In a particular embodiment, the carrier comprises at least one disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, and glycolic acid. Sodium starch glycolate. In a particular embodiment, the disintegrant is crospovidone.

In a common embodiment of each of the aspects described herein, the solid dosage form of the invention is in the form of a tablet. In some embodiments, the tablet is coated. In some embodiments, the tablet is a single layer tablet. In other embodiments, the lozenge is a bilayer tablet. In a particular embodiment, the lozenge of the present invention comprises Pabsiri in an amount of 25 mg, 75 mg, 100 mg or 125 mg. In a particular embodiment, the tablet of the present invention comprises a 125 mg amount of Pabbori.

In a common embodiment of each of the aspects of the invention, the solid dosage form is in the form of a tablet. In some embodiments, the tablet is a single layer tablet. In other embodiments, the lozenge is a bilayer tablet.

In some embodiments of the states and embodiments described herein, in a dosage form The amount of Pabsili in the case is 25 mg, 75 mg, 100 mg or 125 mg. In a particular embodiment, the amount of Pabbori in the dosage form is 125 mg.

Each of the embodiments of the invention described herein may be combined with one or more embodiments of the invention described herein, which are inconsistent with the embodiments.

Figure 1. Prototype formulation containing eight experimental water-soluble acids (malic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, toluenesulfonic acid, benzoic acid, and benzenesulfonic acid) at 50 rpm The spin-leafed USP 2 apparatus was lysed in a test tube at 37 ° C in a 10 mM sodium acetate buffer solution at pH 5.5.

Figure 2. In vitro in vitro dissolution data for a prototype formulation containing succinic acid, malic acid, and tartaric acid in a USP 2 device with blades at 50 rpm spin at 37 ° C in 10 mM sodium acetate buffer at pH 5.5.

Figure 3. Non-leakage (non-) in a 50 mM phosphate buffer solution containing +0.1 M NaCl at pH 6.5 in a USP 2 unit with blades at 50 rpm spin at 37 ° C in a prototype formulation containing succinic acid. Sink) Dissolve data in the tube.

Figure 4. Formulations A1, A2, and B were dissolved in a non-slotted tube in a 50 mM phosphate buffer pH 6.5 containing +0.1 M NaCl at 37 °C in a USP 2 device with 50 rpm spin blades. data.

The present invention may be more readily understood by reference to the preferred embodiments of the invention described hereinbelow. It is understood that the terminology used herein is for the purpose of illustration and description It is to be further understood that the terms used herein are given in their conventional sense as known in the related art, unless specifically defined herein.

As used herein, the singular forms "a", "an", "the" and "the" are meant to include the plural unless otherwise indicated. For example, an excipient includes one or more excipients.

The term "about" means that a value falls within the standard of error that is generally accepted by those skilled in the art. The term "about" is used to mean ±15%, preferably ±10%, and more preferably ±5%, of the value or range recited. For example, about 10% by weight of 〞 means 10% by weight ± 1.5% by weight, preferably 10% by weight ± 1% by weight, and more preferably 10% by weight ± 0.5% by weight.

Unless otherwise indicated, Paporicil refers to 6-acetamido-8-cyclopentyl-5-methyl-2-(5-piperidin The free base of 1-yl-pyridin-2-amino)-8H-pyrido[2,3-d]pyrimidin-7-one, which may be crystalline or amorphous, or a mixture of amorphous and crystalline forms.

The absorption of the drug administered orally can be affected by the pH change of the drug as it passes through the gastrointestinal (GI) tract. Absorption can occur at different locations along the GI tract, such as on the inside of the cheek or in the stomach, duodenum, jejunum, ileum, or colon. The pH at each absorption site is different, and the pH of the stomach (pH 1-3.5) is significantly different from the pH of the small intestine (pH 4.5-8). When drugs pass Over the GI tract, drugs with pH-dependent solubility can precipitate from solution, resulting in a degree of absorption between the dose or patient and/or the rate of absorption between patients or the patient itself.

The pH of the GI tract can also be varied based on whether the patient or subject is in a fed or fasting state. The gastric retention time of the drug is usually longer in the presence of food than in the fasting state. If the bioavailability of the drug is significantly affected by the presence or absence of food in the GI tract, the drug is said to exhibit a licking effect. Gastric emptying rate can also affect the concentration of drug in a solution that is effectively absorbed at different locations along the GI tract.

Certain drugs and medical symptoms (such as no acidosis) that are co-administered may also affect the pH of the GI tract. The use of an acid reducing agent, such as a proton pump inhibitor (PPI) or an H2 receptor antagonist, can result in a relatively high gastric pH, which can result in a drug having pH dependent solubility only partially soluble in the stomach. Further dissolution of the undissolved drug can be inhibited due to the low solubility in the upper pH environment of the upper intestinal tract. This can result in uneven solubilization of the drug with pH-dependent solubility, increasing the risk of drug-drug interaction and possibly resulting in reduced absorption and reduced therapeutic benefit.

Studies in healthy volunteers showed exposure to paclicilil (125 mg administered daily in free base capsules) to eat subjects (AUCinf, 23%-27%; Cmax, 21%-24%) relative Fasting subjects (AUCinf, 39%; Cmax; 73%) slightly increased and greatly reduced PK variability in the fed state. Ruiz-Garcia et al., Annals of Oncology (2014) 25 (suppl_4): iv 146-iv 164.10.1093/annonc/mdu331. Because a decrease was observed in the fed state Inter-patient variability, so it is recommended to take the commercially available Pabsiri free base capsules with food on the US package insert.

When the compounds are formulated into tablets or other solid dosage forms, it is desirable to develop formulations that have storage stability above those typically encountered temperatures and relative humidity levels. Other desirable formulation properties may also be sought, such as rapid dissolution, such that the tablet dissolves rapidly and the drug is effectively absorbed. Therefore, good storage stability and rapid dissolution are especially desirable properties as a desirable feature of the present invention.

Drug dissolution represents a key factor affecting systemic absorption. Various in vitro methods have been developed to assess the solubility properties of pharmaceutical formulations, and dissolution testing is sometimes used as an alternative to directly assessing drug bioavailability. See, for example, Pharmaceutics (2010), Emmanuel et al., 2: 351-363, incorporated herein by reference. The dissolution test measures the percentage of API that is released from the drug product (ie, lozenge or capsule) and dissolved in the dissolution medium for a defined period of time under controlled test conditions. In order to maintain a sink condition, the drug saturation in the dissolution medium should be at least three times the drug concentration. The dissolution of low solubility compounds can sometimes be measured in a non-leaky state. Dissolution is affected by API properties (eg particle size, crystal form, packing density), pharmaceutical product composition (eg drug loading, excipients), manufacturing methods (eg compression forces) and stability under storage conditions (eg temperature, humidity) Impact.

Methods for assessing the chemical storage stability of solid dosage forms under accelerated aging conditions are described in the literature. See, for example, S.T. Colgan, T.J. Watson, R.D. Whipple, R. Nosal, J.V. Beaman, D.De Antonis's "The Application of Science and Risk Based Concepts to Drug Substance Stability Strategies" J. Pharm. Innov. 7: 205-2013 (2012); Waterman KC, Carella AJ, Gumkowski MJ et al., Improved protocol and data analysis for Accelerated Shelf-life estimation of solid dosage forms. Pharm Res 2007;24(4):780-90; and STColgan, RJTimpano, D.Diaz, M.Roberts, R.Weaver, K.Ryan, K. Fields, G "Opportunities for Lean Stability Strategies" by Scrivens, J. Pharm. Innov. 9:259-271 (2014).

The solid dosage form of the present invention, Pabsiri's piperazine The base moiety and the acid adduct of the water soluble acid form an important degradant that is monitored to assess storage stability.

As further described herein, the present invention provides solid dosage forms comprising paclicil, a water soluble acid, and a pharmaceutically acceptable carrier, and methods of making and using same.

Solid dosage forms include, but are not limited to, immediate release tablets and capsules, controlled release (CR) tablets and capsules, fast solvent type, chewable dosage forms, pouches and the like. The dosage form of the invention is preferably in the form of a tablet, including a single layer or a bilayer tablet.

The bismuth solid dosage form of the present invention is a pharmaceutically acceptable solid dosage form for safe oral administration to humans, wherein all excipients in the dosage form are pharmaceutically acceptable for use in oral formulations, in other words, Safe for human ingestion. In a common embodiment, the solid dosage form is a lozenge.

The term unit dose or unit as used herein. Dosage refers to a physically discrete unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect. The unit dosage can be in the form of a tablet, capsule, sachet, or the like, which is referred to herein as a unit dosage form.

The term "empty belly" as used herein is defined as follows: limited to at least 10 hours (ie, 10 hours) The state of administration after an overnight fasting (where 0 calorie intake occurs). Subjects can be administered a dosage form of 240 ml of water. Eating should not be allowed for at least 4 hours after administration. Drinking water as needed may be allowed, except 1 hour before and after the drug is administered.

The term "ingestion" as used herein is defined as follows: after at least 10 hours of overnight fasting (where 0 calorie intake occurs), the subject then begins the recommended state of administration of the meal. Subjects should eat within 30 minutes; however, the drug product should be administered 30 minutes after the start of the meal. The drug product can be administered in 240 ml of water. Eating should not be allowed for at least 4 hours after administration. Drinking water as needed may be allowed, except 1 hour before and after the drug is administered.

To assess the feeding/fasting ratio, a single oral dose of Pabsiri can be administered: in a high-fat, high-calorie diet (~800-1000 calories, with 150, 250, and 500-600 from protein, carbohydrate, and fat, respectively) 30 minutes after calories; 30 minutes after a low-fat, low-calorie diet (~400-500 calories with 120, 250, and 28-35 calories from protein, carbohydrate, and fat, respectively); or between proper fat and A meal of calorie-rich meal (~500-700 calories consisting of 15% protein, 50% carbohydrates, and 35% fat) (1 hour later / 2 hours before).

High fat and high calorie meals are available as a test meal in the fed state. Examples of high fat test meals are two milk-fried eggs, two bacon, two creamy toasts, four ounces of potato wedges, and eight ounces of whole milk.

The calculation of the area under the mean serum concentration versus time curve (AUC) is a procedure well known in the medical arts and is described, for example, in Welling, "Pharmacokinetics Processes and Mathematics," ACS Monograph 185 (1986). AUC as used herein includes the area under the concentration-time curve extrapolated from time 0 to infinity after a single dose or under a concentration-time curve from time 0 to the end of the dosing interval after steady state/multiple doses Area.

In addition, the calculation of C _max , C _{min, ss} , T _max and the elimination half-life (t1⁄2) is also known to those skilled in the art and is described, for example, in Shargel, Wu-Pong, and Yu, Applied Biopharmaceutics and Pharmacokinetics (2005). in.

In order to determine the average feeding/fasting ratio, the average area under the plasma concentration versus time curve of the pascaliri in the fed state (for example, AUC _0-inf ) was calculated for the plasma concentration versus time curve of the pasoriberi in the fasting state. The individual ratios of the average areas (e.g., AUC _0-inf ) are then averaged together for the corresponding individual ratios. In this manner, it is the average of the respective individual ratios determined.

Proton pump inhibitors (PPIs) are well-known classes of drugs that reduce gastric acid production, thereby modifying gastric pH. Representative PPIs include, for example, rabeprazole, omeprazole (including S- and B-forms, Na and Mg) Salt), lansoprazole, pantoprazole, eseprazole and the like.

As used herein, the term "immediate release type (IR) oral capsule" refers to a commercially available Pabsiri IR capsule formulation as described in Example 11. This formulation lacking a water soluble acid, but otherwise substantially identical to the formulation of Example 1, can be referred to herein as a control together with the isethionate formulation (ISE) and the free base lozenge dosage form.

〝 Dissolution test 1 〞 refers to the following test of the Pabsiri dosage form. The dissolution test is carried out in a standard USP 2 rotary vane apparatus as disclosed in the United States Pharmacopoeia (USP) Dissolution Test Chapter 711, apparatus 2. The leaves were spun at 50 rpm and the dosage form was added to 500 ml of 10 mM pH 5.5 acetate buffer at 37 °C. The filtered aliquot (usually 1.5 ml) from the test medium was analyzed by high performance liquid chromatography (HPLC) at the appropriate time after the start of the experiment (eg in the dosage form insertion device). The dissolution results are reported as the percentage of dissolution of the total dose of Pabsiri tested over time.

〝 Dissolution test 2 〞 refers to the following test of the Pabsiri dosage form. The dissolution test was carried out in the USP 2 rotary vane apparatus of the standard disclosed in the United States Pharmacopoeia (USP) dissolution test section 711, apparatus 2. The leaves were spun at 50 rpm and the dosage form was added to 500 ml of 50 mM phosphate buffer pH 6.5 and 0.1 M NaCl at 37 °C. The filtered aliquot (usually 1.5 ml) from the test medium was analyzed by high performance liquid chromatography (HPLC) at the appropriate time after the start of the experiment (eg in the dosage form insertion device). The dissolution result was measured by the total dose of Pabsiri tested. The percentage of dissolution relative to time is described.

The term "dry granulation" means a method of blending a host active product with at least one excipient. The blend is then compressed or compacted to form a compressed material or crucible compact. This material can be split into anhydrous particulate particles by crushing, grinding or cutting to form granules. The particles can be further processed at will. The crushing, grinding or cutting process involves the operation of reducing the size of the compressed material, such as by grinding or other operations known to those skilled in the art.

The term "water-soluble oxime" as used herein in connection with the acid present in the composition refers to an acid having a solubility in water of at least 0.2% by weight at 25 °C. The water-soluble acid may be an organic or inorganic acid, and is preferably an organic acid having at least one pKa value, the value being at least one (preferably at least two) higher than the highest pKa of the basic group present in the drug. Small pK unit. In the case of Pabbori, the water soluble acid has a pKa of about 4.1 and 7.3, and the acid preferably has a pKa of less than 6.3, and more preferably a pKa of less than 5.3. The water-soluble organic acid includes, for example, a C ₂ -C ₈ or C ₂ -C ₆ aliphatic mono or polycarboxylic acid, and is preferably a C ₄ -C ₆ aliphatic mono or polycarboxylic acid. Particularly preferred is a C ₄ -C ₆ dicarboxylic acid which may be saturated or unsaturated.

The solid dosage form of the invention may comprise a single water soluble acid or may comprise a combination of two or more such acids. In an alternative embodiment of the invention, the water soluble acid is selected from the group consisting of succinic acid, malic acid and tartaric acid. In a particular preferred embodiment of the invention, the water soluble acid is succinic acid.

The water-soluble acid can be combined with the drug before granulation or can be shaped outside the particle The agents are incorporated together into a dosage form. In the bilayer tablet, the water-soluble acid may be present in the active layer containing pabsoli, incorporated into a separate acid layer, or the water-soluble acid (which may be the same or different) may be incorporated into the active layer and the acid layer. In both.

Without wishing to be bound by theory, it is believed that the acid present in close contact with the drug in a solid dosage form increases dissolution by the interaction between pabbice and acid. After oral administration to a subject, the solid dosage form of the present invention thus provides for increasing the local concentration of the drug in the solution as compared to administering a Pabsiri formulation lacking the water soluble acid.

In some embodiments, the solid dosage form of any of the embodiments described herein is dissolved under the conditions of Dissolution Test 1 (pH 5.5 acetate buffer, 37 ° C): (a) within 15 minutes. Not less than 35% of Pabori; (b) not less than 45% of Pabori in 30 minutes; (c) not less than 55% of Pabori in 60 minutes; or (d) (a Two or more of), (b) and (c).

In another embodiment, the solid dosage form of the invention is dissolved under the conditions of dissolution test 1: (a) not less than 25%, 30%, 35%, 40%, 45% or 50% or more than 50% Pabsili dissolves within 15 minutes; (b) not less than 35%, 40%, 45%, 50%, 55% or 60% or more than 60% of the Pabsili dissolves within 30 minutes; and / or c) Not less than 45%, 50%, 55%, 60%, 65% or 70% or more than 70% of the Pabsili dissolves within 60 minutes.

In some embodiments, the solid dosage form of any of the embodiments described herein is dissolved in a non-leaked state of Dissolution Test 2 (pH 6.5 phosphate buffer and 0.1 M NaCl, 37 ° C): (a) within 15 minutes Not less than 40% of Pabsiri; (b) not less than 35% of Pabori in 30 minutes; (c) not less than 25% of Pabori in 60 minutes; or (d) (a Two or more of), (b) and (c).

In other embodiments, the solid dosage form of any of the embodiments described herein is dissolved in a non-leaked state of Dissolution Test 2 (pH 6.5 phosphate buffer and 0.1 M NaCl, 37 ° C). : (a) not less than 15% of Pabori in 15 minutes; (b) not less than 20% of Pabori in 30 minutes; (c) not less than 25% of Pabo in 60 minutes Siri; or (d) two or more of (a), (b) and (c).

In other embodiments, under dissolution test 2: (a) not less than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% or more than 50% Pabsili dissolves in 15 minutes; (b) not less than 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% or more than 50% of Pabbori in 30 minutes Dissolved internally; and/or (c) not less than 15%, 20%, 25%, 30%, 35% or 40% or more than 40% of the Pabsili dissolved within 60 minutes.

In another embodiment, under dissolution test 2: (a) not less than 30%, 35%, 40%, 45% or 50% or more than 50% of the Pabsili dissolved within 15 minutes; (b ) not less than 25%, 30%, 35%, 40%, 45% or 50% or more than 50% of Pabsili dissolved in 30 minutes; and / or (c) not less than 15%, 20%, 25%, 30%, 35% or 40% or more than 40% of the Pabsili dissolved in 60 minutes.

In some embodiments, the invention provides a solid dosage form comprising a paclitaxel, a water soluble acid, and a pharmaceutically acceptable carrier, wherein the dosage form provides: (a) in a plasma after administration of a single oral dose to the subject The area under the concentration versus time curve (AUC) is from an average eating/fasting ratio of from about 0.8 to about 1.25; (b) the maximum plasma concentration ( _Cmax ) from about 0.8 to about 1.25 after administration of a single oral dose to the subject. Average eating/fasting ratio; or (c) both (a) and (b).

In some embodiments, the invention provides a solid dosage form comprising a paclitaxel, a water soluble acid, and a pharmaceutically acceptable carrier, wherein the dosage form: (a) provides a content after administration of the subject to a single oral dose, etc. Effectiveness of the Pabsiri control average fasting AUC in the range of 80% to 125% of the average fasting AUC of immediate release (IR) oral capsules; (b) after administration of a single oral dose to the subject Pabo Xi provided in the control contained equivalent amounts with immediate-release (IR) by an average of 80 to 125% of the opening of the capsule fasting average of the range of fasting plasma C _max C _max; or (c) (a) and ( b) Both.

In a further embodiment, the invention provides a solid dosage form comprising a paclitaxel, a water soluble acid, and a pharmaceutically acceptable carrier, wherein the dosage form provides: (a) after administration of a single oral dose to the subject The average AUC in the presence of a proton pump inhibitor (PPI) (preferably rabeprazole) is in the range of 80% to 125% of the mean AUC in the absence of PPI; (b) in a single subject after oral doses via the proton pump inhibitor (PPI) (preferably azole Ruibei La) present in the system mean C _max in the range of 80 to 125% of the average C _max of the PPI in the absence of presence; or (c Both (a) and (b).

In other embodiments, the present invention provides for inclusion of Pabbori, water a solid dosage form of a soluble acid and a pharmaceutically acceptable carrier, wherein the dosage form exhibits less than 0.4%, 0.35%, 0.3%, 0.25%, 0.2% after storage for 96 days at 30 ° C and 75% relative humidity (RH), 0.15% or 0.1% by weight acid adduct.

In still other embodiments, the present invention provides a solid dosage form comprising a paclitaxel, a water soluble acid, and a pharmaceutically acceptable carrier, wherein the dosage form exhibits less than 1.5 after storage for 2 years at 30 ° C and 75% RH. %, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4% or 0.3% by weight of the acid adduct.

In some embodiments of each of the aspects and embodiments of the invention, the water soluble acid is selected from the group consisting of succinic acid, malic acid, and tartaric acid. In a particular embodiment of each of the aspects and embodiments herein, the water soluble acid is succinic acid. In other embodiments, the water soluble acid is malic acid. In another embodiment, the water soluble acid is tartaric acid.

In some embodiments of each of the aspects of the invention, the water soluble acid comprises from about 5% to about 40% by weight of the solid dosage form. In a particular embodiment, the water soluble acid comprises from about 5% to about 25% by weight of the solid dosage form. In some embodiments, the water soluble acid constitutes about 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40% by weight of the solid dosage form.

In some embodiments of each of the aspects of the invention, the pablocillin constitutes from about 10% to about 35% by weight of the solid dosage form. In a particular embodiment, the Pabsili constitutes about 20% by weight of the solid dosage form. In some embodiments, the Pabsili constitutes about 5 weights of the solid dosage form. %, 10% by weight, 15% by weight, 20% by weight, 25% by weight, 30% by weight, 35% by weight, 40% by weight, 45% by weight or 50% by weight.

In a common embodiment of each of the aspects and embodiments herein, the solid dosage form is a tablet, preferably a tablet formed by dry granulation. In some such embodiments, the lozenge is a bilayer tablet. In a particular embodiment, the bilayer tablet comprises: (a) an active layer comprising paclicil and a pharmaceutically acceptable carrier; and (b) comprising a water soluble acid and a pharmaceutically acceptable carrier Acid layer. In some embodiments, the bilayer tablet comprises: (a) an active layer comprising a Pabsili, a water soluble acid, and a pharmaceutically acceptable carrier; and (b) comprising a water soluble acid and a pharmaceutically acceptable The acid layer of the carrier wherein the water soluble acid in the active layer can be the same or different than the water soluble acid in the acid layer. In a particular embodiment, the water soluble acid in the active layer is succinic acid and the water soluble acid in the acid layer is tartaric acid.

In another aspect, the invention provides a method of treating cancer comprising administering a therapeutically effective amount of a solid dosage form of any of the conditions and embodiments described herein to a subject in need thereof. In a particular embodiment, the cancer is breast cancer. In some such embodiments, the breast cancer is a hormone receptor positive (HR+) breast cancer. In some such embodiments, the breast cancer is an estrogen receptor positive (ER+) breast cancer. In some such embodiments, the breast cancer is human epidermal growth factor receptor 2 negative (HER-) breast cancer. In other such embodiments, the breast cancer is human epidermal growth factor receptor 2 positive (HER+) breast cancer. In another embodiment, the breast cancer is advanced or metastatic breast cancer that can be characterized by HR+, HER2- or ER+, HER2-.

Pabsili can be administered alone or in combination with other drugs, particularly aromatase inhibitors, such as letrozole, fulvestrant or exemestane, and are usually pharmaceutically acceptable with one or more Formulations associated with excipients are administered. The term "excipient" refers to any ingredient other than paclocil or its salt.

Paphosili can be administered orally. Oral administration can include swallowing such that the compound enters the gastrointestinal tract, or can be administered intravesically or sublingually, thereby allowing the compound to enter the bloodstream directly from the mouth.

The dosage form of the invention can be administered to a subject in need of such treatment in a therapeutically effective amount. The term "therapeutically effective amount" as used herein refers to an amount of a compound to be administered which relaxes one or more of the symptoms of the condition to be treated to some extent. A therapeutically effective amount for cancer treatment refers to an amount that has the following effects: (1) reducing tumor size, (2) inhibiting (i.e., slowing down to some extent, preferably stopping) tumor metastasis, and (3) inhibiting (also That is, slowing down to some extent, preferably stopping) tumor growth or tumor invasion to some extent, and/or (4) slowing down one or more signs or symptoms associated with cancer to some extent (or preferably eliminate).

A sputum sputum as used herein refers to a human or animal subject. In certain preferred embodiments, the subject is a human. In some embodiments, the subject is a patient suffering from a disease state. In other embodiments, the subject can be a healthy volunteer.

The term "treating" as used herein means reversing, alleviating, inhibiting the progression of a condition or condition to which the term applies or the progression of one or more symptoms of such condition or condition, or preventing the above described condition or condition, unless There are other instructions. The term "treatment" as used herein refers to the act of treatment just as defined above, unless otherwise indicated. The term "treatment" also includes adjuvant and neoadjuvant treatment of the subject. Pabsili can be administered alone or in combination with an aromatase inhibitor, such as letrozole, fulvestrant or exemestane.

As used herein, sputum cancer refers to any malignant and/or invasive growth or tumor caused by abnormal cells. As used herein, a sputum cancer refers to a solid tumor named after a cell type that forms a cancer (for example, breast cancer), and a blood cancer, a bone marrow cancer, or a lymphatic system cancer. Examples of solid tumors include, but are not limited to, sarcomas or carcinomas. Examples of blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. The term "carcinoma" includes, but is not limited to, primary cancer derived from a specific location in the body, metastatic cancer that spreads from the beginning to other parts of the body, recurrence from the original primary cancer, and a second primary Sexual cancer (which is a neonatal primary cancer in a patient with a different preclinical history than a later cancer).

More specifically, examples of cancers associated with the present invention, preferably in combination with an aromatase inhibitor, include, in particular, breast cancer. For example, the cancer can be a hormone receptor positive (HR+) breast cancer, and in particular an estrogen receptor positive (ER+) breast cancer. In some embodiments, the ER+ breast cancer is human epidermal growth factor 2 (HER2)-negative. In another embodiment, the cancer is ER+, HER2-advanced metastatic breast cancer, wherein the drug is administered in combination with an aromatase inhibitor for treating a metastatic disease.

Formulations suitable for oral administration include solid formulations such as lozenges, capsules, powders, diamond ingots (including filling with liquids), pouches and the like. Like. In a preferred aspect of the invention, the solid dosage form provided herein is a tablet. In some such embodiments, the tablet is encapsulated. In other such embodiments, the lozenge is a bilayer tablet.

The paclitaxel used in the lozenge dosage form may comprise from 1% to 80% by weight of the dosage form depending on the dosage, typically from 5% to 60% by weight of the dosage form, more typically from about 10% by weight of the dosage form. From about 15% by weight to about 35% by weight, or even more typically from about 15% to about 25% by weight of the dosage form. In a particular embodiment, the Pabsili constitutes about 20% by weight of the dosage form.

In the solid dosage form of the present invention, the carrier may contain various pharmaceutically acceptable excipients including, for example, diluents, disintegrating agents, binding agents, lubricants, slip agents, and surfactants. Formulations may also include excipients such as preservatives, antioxidants, perfumes, and coloring agents, as well as other excipients known in the art.

Solid dosage forms such as lozenges typically contain diluents such as lactose (single hydrate, spray dried monohydrate, anhydrate, and the like), mannitol, xylitol, glucose, sucrose, sorbitol, compressible Sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, polygluconate, polydextrose, dextrin, glucose, maltodextrin, calcium calcium phosphate, calcium hydrogen phosphate, calcium phosphate, calcium sulfate , magnesium carbonate, magnesium oxide, poloxamer, polyethylene oxide, hydroxypropyl methylcellulose, and mixtures thereof. Different types of microcrystalline cellulose are suitable for use in the formulations described herein. Examples of microcrystalline cellulose include Avicel® type: PH101, PH102, PH103, PH105, PH 112, PH113, PH200, PH301, and other types of microcrystalline cellulose, such as deuterated microcrystalline cellulose (SMCC). In some embodiments, the diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesium carbonate, calcium hydrogen phosphate, calcium phosphate or mixture. In a particular embodiment, the diluent comprises microcrystalline cellulose. In some embodiments, the diluent comprises one or more types of microcrystalline cellulose, such as Avicel® PH105, Avicel® PH200, or mixtures thereof. In some such embodiments, the diluent does not include lactose monohydrate. In other such embodiments, the diluent comprises microcrystalline cellulose and additionally comprises lactose monohydrate. The diluent often constitutes from about 25% to about 75% by weight of the solid dosage form, and preferably from about 50% to about 75% by weight of the dosage form.

Solid dosage forms often contain a disintegrant. Examples of the disintegrant include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose. , microcrystalline cellulose, low carbon alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. In some embodiments, the disintegrant is crospovidone. Any grade of crospovidone can be used; for example, CL, CL-SF, and XL grade crospovidones are suitable for use in the formulations described herein. Specific examples include Kollidon, Kollidon CL®, Kollidon CL-M®, Polyplasdone XL®, Polyplasdone XL-10®, and Polyplasdone INF-10®. In some embodiments, the carrier comprises at least one disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, and sodium starch glycolate. In a particular embodiment, the disintegrant is Cross-linked povidone. The disintegrant will often comprise from about 1% to about 25% by weight of the dosage form, preferably from about 5% to about 20% by weight, more preferably from about 5% to about 10% by weight.

The binding agent can be used to impart viscosity to the formulation of the tablet. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. In some embodiments, the binding agent is selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. In a particular embodiment, the binding agent is microcrystalline cellulose, such as Avicel® PH105. When present in the presence of a binding agent, it can comprise from about 0% to about 15% by weight of the dosage form, or from about 0.2% to about 10% by weight. In some embodiments, the binding agent comprises from about 5% to about 10% by weight of the dosage form. In a particular embodiment, the binding agent comprises about 10% by weight of the dosage form.

Solid dosage forms often contain one or more lubricants. Examples of the lubricant include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium lauryl sulfate or two or more of these. mixture. In some embodiments, the lubricant is magnesium stearate and/or sodium stearyl fumarate. In some embodiments, the lubricant is magnesium stearate. In some such embodiments, the solid dosage form is a lozenge comprising intragranular and extragranular magnesium stearate. In other embodiments, the solid dosage form is a lozenge comprising intragranular magnesium stearate and extragranular stearyl fumarate. When present, the lubricant will generally comprise from about 0.25 wt% to about 10 wt%, preferably from about 0.5 wt% to about 6 wt%, of the dosage form.

Tablets may also contain slip agents such as cerium oxide, colloidal cerium oxide, magnesium ruthenate, magnesium tricaprate, talc and other forms of cerium oxide such as aggregate citrate and hydrated cerium oxide. In some embodiments, the slip agent is cerium oxide. When present in the presence of a slip agent, it may comprise from about 0% to about 10% by weight of the tablet, preferably from about 0.2% to about 5% by weight, or from about 0.5% to about 2% by weight. .

The tablet may optionally include a surfactant such as sodium lauryl sulfate and polysorbate 80. When present in the presence of a surfactant, it may constitute from 0% to 10% by weight of the tablet, or preferably from 0.2% to 5% by weight.

The solid dosage form of the invention is typically prepared according to methods common in pharmaceutical chemistry. The selected excipient can be incorporated into either or both of the extragranular or intragranular compartments with the API.

Exemplary lozenge formulations contain from about 10% to about 35% by weight of Pabbori, typically from about 15% to about 25% by weight of Pabburi; from about 5% to about 15% by weight a water-soluble acid; from about 25% by weight to about 75% by weight of a diluent; from about 5% by weight to about 10% by weight of a disintegrant; from about 0.5% by weight to about 6% by weight of a lubricant; and optionally From about 0% by weight to about 5% by weight of the slip agent; and from about 0% by weight to about 15% by weight of the binder.

Further exemplary lozenge formulations contain about 20% by weight of Pabsili; about 10% by weight of water soluble acid (preferably succinic acid); from about 50% by weight to about 75% by weight of diluent (preferably Microcrystalline cellulose); from about 5% by weight to about 10% by weight of a disintegrant (preferably cross-linked poly-dimensional) Ketone); from about 0.5% by weight to about 6% by weight of a lubricant (preferably magnesium stearate or sodium stearyl fumarate or both); optionally from about 0% by weight to about 5% by weight a slip agent; and optionally from about 0% to about 15% by weight of the binder. When a slip agent is present, it is preferably cerium oxide, and when a binder is present, it is preferably a suitable type of microcrystalline cellulose (e.g., Avicel® PH105) that becomes a waterless binder.

Oral formulations for oral administration can be formulated for immediate and/or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and stylized release. For a general description of modified release formulations, see U.S. Patent No. 6,106,864.

Pharmaceutical products in the form of solid shaped lozenges are typically made by compressing the materials that make up the final product into the desired lozenge form. Such materials may include active pharmaceutical ingredients as well as pharmaceutically inactive excipients that impart necessary or useful properties to the product during or after the manufacturing process. Tablet hardness or tensile strength can be used as a measure of the stickiness of the tablet ingredients. If the tablet does not have sufficient bonding properties, the tablet may split during processing. The final formulation may comprise one or more layers and may or may not be enveloped.

As is known in the art, granulation is a method for improving the handling and manufacturing properties of a formulation, such as by increasing the particle size to improve flow. Granulation does not substantially alter the physical form of the drug, such as its crystalline or amorphous character. Tablet formulations are prepared by those skilled in the art using a variety of methods. Examples of such methods include dry granulation, wet granulation, fluid bed granulation, and direct compression. The type of method used may depend on factors such as the physical characteristics of the active pharmaceutical ingredient in the formulation, the excipients used. The desired physical characteristics of the type and final product. Each of these methods includes the step of mixing the ingredients of the dosage form. In a particular embodiment of the invention, dry granulation is preferred.

It is often necessary to mix a certain amount of the dosage form ingredients in order to have a uniform and consistent final product. However, when pharmaceutical tablets were prepared by wet and dry granulation, it was found that the degree of mixing and strength of the components before compression was related to the compressibility and adhesion loss of the formulation, resulting in a decrease in the hardness of the tablet.

Similar results were observed when rolling in real time, such as in a dry granulation process. Roll compaction can be used as a method of forming particles which are subsequently compressed into a tablet. Roll compaction reduces subsequent compressibility and adhesion of the dosage form.

Dry granulation is a method of forming granules in a compacting step, followed by grading the compact into particles that are easily processable. This method is often used to improve the flow properties and/or density of the formulation, which can accelerate further manufacturing processes such as tableting, encapsulation, and powder filling. The compact is made directly from a powder blend which typically contains the active ingredient and other excipients, including lubricants.

The use of dry granulation technology is superior to wet granulation because of the short processing time and cost advantages. However, dry granulation is generally limited by those in which the drug or active ingredient has physical characteristics suitable for the formation of pharmaceutically acceptable granulates and dosage forms such as troches.

It is usually necessary to add at least one excipient to the formulation, and this addition results in an increase in the size of the lozenge of the final product. When the size of the lozenge must be within a specific range of parameters that function in a suitable dosage form, it is not possible to accommodate an increased tablet size beyond the limit in order to accommodate the increased amount of excipients that increase the compactability. OK. Thus, the manufacturer is often limited to dry granulation for each compressed tablet containing a formulation of a low dose of active ingredient such that the formulation can hold an amount of excipient sufficient to effect dry granulation.

In the development of pharmaceutical dosage forms, it is important to balance many different goals. It is important to prepare the pharmaceutical dosage form as much as possible in an economical manner. It may be desirable to have a simple process involving several processing steps. The dosage form should also provide optimal availability of the active compound contained therein to the patient. Furthermore, the dosage form should be easy to swallow. The smaller the dosage form, the easier it is to be accepted by the patient and the patient's adaptability can be improved.

The final pharmaceutical composition is processed into a unit dosage form (eg, a lozenge or capsule) and then packaged for sale. The processing steps vary depending on the particular unit dosage form. For example, tablets are typically compressed under pressure into the desired shape and the capsules are used in a simple filling operation. Those skilled in the art are familiar with procedures for making various unit dosage forms.

Tablets are usually formed by applying pressure to the material of the tablet to be used in the tablet. The formulation must have good flow properties that allow the material to be fed into the mold cavity in an accurate volume, and have compressibility, compressibility, and pop-up properties suitable for forming a tablet.

There are many presses with different productivity, but the basic functions and operations are similar. All tablet presses compress the tablet formulation in the mold cavity by the pressure applied between the two stainless steel punches (the upper punch and the lower punch). The tablet press is typically designed to have a hopper containing the feed formulation, feed the formulation into the die and adjust the feed mechanism for the punch and die positioning, and to guide the punch movement in the rotary press. Cam track. Two Types of presses are single-station or single-punch presses and multi-station rotary presses. Some presses offer longer residence times than others and can occur with increased bonding. Other presses provide pre-compression.

Wet granulation methods can also be used to prepare granules of pharmaceutical compositions. Wet granulation methods are described in Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 19th Edition 1995. These and other methods are generally known to those skilled in the art. If wet granulation is used, the volatizing agent can be incorporated into the mixture before, during or after mixing of the ingredients, but prior to forming the granules. For example, the solid volatile agent can be blended with the powder mixture before, during or after the addition of the binder solution. Other solid dosage forms can be prepared using techniques including rotary bed granulation or spray dried dispersion (SDD).

The invention will be exemplified in the following non-limiting examples.

Example Example 1 Free base plus succinic acid

Tablets containing API (Pabori) in the form of the free base with dry granulation of succinic acid were prepared using the following procedure. Tablets have the composition in Table 1.

Microcrystalline cellulose (Avicel PH105) was added to a blender (box blender or equivalent) and mixed at low speed for about 25 revolutions (12 minutes at 12 rpm). The API was added to the blender and the API container was rinsed with a portion of the lactose monohydrate and folded and mixed. A batch amount of succinic acid, lactose monohydrate, crospovidone and colloidal cerium oxide was added to the blender which was mixed at about 180 rpm (for 15 minutes at 12 rpm) at low speed.

The attritor and bag were precoated with a 50% batch amount of microcrystalline cellulose (Avicel PH102). The blend from the above was passed through a attritor. The attritor was rinsed with the remainder of the microcrystalline cellulose (Avicel PH102) and the ground material was transferred from the bag to a blender (box blender or equivalent) and passed at about 180 rpm at low speed. (mixed at 12 rpm for 15 minutes). The intragranular magnesium stearate is sieved through a suitable grading sieve and added to the previous step In the blending machine. The mixture was mixed at low speed for about 60 revolutions (for 12 minutes at 12 rpm). The blend is compacted by roller (Gerteis Minipactor or equivalent) without separating or recovering the fines. If in-line grinding is not used, the roll compacted blend is passed through a Comil U5 or U10 equipped with a 1601 impeller, a 050G mesh, and a speed of 1000 or 700 rpm, respectively.

The granules of diplomatic vidosterone were added to the blender of the previous step. The mixture was mixed at low speed for about 180 revolutions (for 12 minutes at 12 rpm). The extragranular magnesium stearate is sieved through a suitable grading sieve. It was added to the blender of the previous step and mixed over about 60 revolutions (5 minutes at 12 rpm).

Tablets are formed using a single station (Korsch XP 1 or equivalent) or a rotary tablet press.

Example 2 Double-layer tablet formulation

A bilayer tablet containing an active layer and an acid layer is prepared. The active layer consisted of the granulated blend from Example 1.

The active layer and the double layer have the compositions in Table 2.

The acid layer blend is formed by combining microcrystalline cellulose, tartaric acid, and crospovidone into a suitable grading vessel. The composition was blended at about 120 revolutions and then passed through a Comil U5 or U10 equipped with a 1601 impeller, a 018R mesh, and a 1000 or 700 rpm speed, respectively.

The ground material was transferred to a blender and the components were then blended over about 120 revolutions. Magnesium stearate was sieved through a suitable graded sieve (1 mm sieve, US Sieve #20), then added to the blender and blended at about 50 revolutions.

The bilayer tablet was formed using the following procedure using a suitable rotary double laminating machine such as Korsch XP1. The active layer granules (formed according to the procedure outlined in Example 1) were compressed to a weight of 625 mg of the active layer and a recommended thickness of 6.66 mm of active layer. The acid layer blend was added and the acid layer and active layer were compressed to a desired filling weight of 985 mg.

Example 3 Fluid bed granulation

Fluid bed coater (Niro MP-2 Fluid Bed Coater, equipped with The MP-1 ball, top spray granulation installation) was preheated using the following conditions until the inlet air dew point (12 ° C) and the product bowl temperature (greater than or equal to 45 ° C) stabilized to the nominal value. The nozzle was a Schlick 970 with a 0.8 mm liquid tip and a nozzle to bowl bottom distance of 33 cm.

To form a fluid bed granulate, succinic acid was first manually ground using a mortar and pestle. The ground powder was periodically placed on a #60 mesh screen and the material was passed through to the collection container using manual shaking. The material remaining on the sieve is returned to the mortar and more unground material is added. Continue to grind until the desired amount passes through the sieve.

In addition to succinic acid, each of the following anhydrous bed components was individually screened through the #30 mesh to their separate collection containers in the desired amounts.

The binder suspension is formed by adding water to a suitable grading vessel. Mannitol and hydroxypropyl cellulose are then added to the container. The solution was mixed for a minimum of 2 hours and no aggregates were visible.

The API is then slowly added to the solution to form a binding agent suspension. The binder suspension is stirred during processing until use. The binder suspension contained the following components in Table 4:

After the fluid bed product bowl temperature has stabilized, the anhydrous bed material is then loaded into the fluid bed in the following order: mannitol, microcrystalline cellulose, succinic acid, and crospovidone.

Fluid bed granulation is initiated at a bed temperature of 29-31 ° C, a spray rate of 12-30 g/min, a flow of 70-115 CMH (m ^ 3 /hr) and an atomization pressure of 1.1 bar to provide fluid bed granulation Compound.

Example 4 Fluid bed granule lozenge

Tablets were formed from the fluid bed granules (FBG) of Example 3 using the following procedure. The granulate was first dry classified by passing the granules through a Comil U5 equipped with a 1601 impeller, a 018R mesh and a speed of 1500 rpm. The particles were visually rated as homogeneously as possible into the Comil (2 kg granules for 20 to 25 minutes). The ground granules are passed through a #60 mesh screen and the material passing through the screen is collected in a bag and placed aside. The material remaining on #60 mesh was ground a second time in Comil. The ground granules were passed through a #60 mesh screen and the material was collected in a bag. Will be second The material remaining on the #60 mesh screen after the second was gently pushed through the sieve using a spatula/scraper until all passed. Add material to the bag.

The final tablet blend of the FBG lozenge is given in Table 5:

If necessary, the adjusted weight of the extragranular component is calculated based on the total weight of the ground particles from the previous step.

The succinic acid was manually ground in small aliquots (for mortar and pestle). Use a sufficient amount to ensure a sufficient amount of ground material. The ground material was passed through a #60 mesh screen and collected in a new bag. Any material remaining on the sieve is returned to the mortar having the next aliquot. The required amount of ground succinic acid is subdivided.

Next, the microcrystalline cellulose and crospovidone were passed through a #30 mesh screen and added to the blender. The ground succinic acid and dry graded fluid bed granules are added to a suitably graded blender. The packing density was 0.39 g/ml. The mixture was mixed at 16 rpm (180 rpm) for 11.25 minutes.

Next, magnesium stearate was combined with 3 to 10 times (by volume, visually assessed) the blend from the previous step in a suitably graded bottle. Will mix The mixture was gently shaken by hand for about 30 seconds and then passed through a No. 30 mesh screen. The contents were added to the blender and mixed at 16 rpm (60 rpm) for 3.75 minutes.

The batch is compressed into the nominal specifications using a suitable tablet press, such as the Korsch XM12.

Example 5 Spray drying dispersion

The hydroxypropyl methylcellulose (HPMC E3 Prem) solution was prepared as follows: 3.25 wt% of HPMC E3 was dissolved in a 90/10 methanol/water (w/w) solvent blend to form 3.2 wt%. HPMC solution. A sufficient amount of Pabsiri (API) was added to this solution to form a spray suspension of the following composition: 1.75 wt% API, 3.25 wt% hydroxypropyl methylcellulose, 85.5% by weight methanol, and 9.5 wt. % of water. The suspension is then continuously stirred to prevent the API from settling in the suspension tank.

The spray dryer was preheated using a heated drying gas (nitrogen) at a flow rate of 1850 g/min and an inlet dry gas temperature of 130 °C. A 90/10 (w/w) methanol/water blend was sprayed after preheating until steady state thermodynamic conditions were reached. Once the spray dryer reached a steady state, the spray suspension was then introduced into the spray dryer via flash atomization at a feed rate of 130 grams per minute, a solution temperature of 130 ° C, and a pressure of 250 psi. A second stream of nitrogen at a pressure of 60 psi was used around the nozzle to prevent nozzle fouling. At the outlet of the spray dryer at a temperature of 45 ° C Set particles.

After collection, the particles were placed in a convection tray dryer operating at 40 ° C / 15% relative humidity for a minimum of 6 hours. This reduces the residual solvent in the particles to no more than 0.3% by weight of residual methanol.

The particle size of the second dried particles was measured using a Malvern Particle Size Analyzer from Malvern Instruments Ltd. of Framingham, Mass., using a low dispersion pressure of 0.5 to 1.0 bar, where D(4,3) is the volume average diameter; DV ₁₀ is The composition comprises a diameter of 10% of the total volume of the particles; DV ₅₀ is the diameter of the composition comprising 50% of the total volume of the particles; and DV ₉₀ is the diameter of the composition comprising 90% of the total volume of the particles. The particle sizes are given in Table 6:

The particle span (DV _{90 -} DV ₁₀ ) / DV ₅₀ was 1.96. The bulk ratio of the particles was 5.6 ml/g, and the tapped specific volume was 3.0 ml/g.

The glass transition temperature (Tg) of the particles as measured by differential scanning calorimetry (DSC) at less than 5% relative humidity was 117.5 °C. Powder X-ray diffraction (PXRD) shows that the API is amorphous with no detectable crystallinity. Such as particle morphology measured by scanning electron microscopy (SEM) Show particles with intact and collapsed spheres.

Example 6 Comparative spray-dried dispersion lozenge

Tablets lacking a water soluble acid were formed from the spray dried dispersion (SDD) of Example 5 using the following procedure. A half amount of microcrystalline cellulose was added to the blender (box blender or equivalent) and mixed at low speed for about 25 revolutions (2 minutes at 12 rpm). Add SDD to the blender. The blender was rinsed with a portion of sodium chloride and mixed.

A batch amount of sodium chloride, croscarmellose sodium, and colloidal ceria was added and mixed at about 180 rpm (for 15 minutes at 12 rpm) at low speed. The final blend is given in Table 7:

Pre-coating the attritor and bag with microcrystalline cellulose in an amount of 25% by weight cloth. The blend from the above procedure was passed through a grinder equipped with a 1601 impeller, a mesh of 032R and a Comil U5 at a speed of 1000. The attritor is rinsed with the remaining batch portion of microcrystalline cellulose and the ground material is transferred from the bag to a blender (box blender or equivalent) and at about 180 revolutions at low speed ( Mix at 12 rpm for 15 minutes).

The intragranular magnesium stearate was sieved through a suitable grading sieve and added to the blender of the previous step, followed by mixing at about 60 revolutions (5 minutes at 12 rpm) at low speed.

The blend was compacted using Korsch XP 1 or equivalent.

The compacted blend was passed through a grinder equipped with a 1601 impeller, a 050 G mesh and a speed of 1000 Comil U5.

The granulate is transferred from the bag to a blender (box blender or equivalent). The amount of extragranular colloidal ceria was calculated and added to the blender of the previous step, followed by mixing at about 180 revolutions (15 minutes at 12 rpm). The amount of extragranular magnesium stearate required was calculated, sieved through a suitable graded sieve and added to the blender of the previous step, followed by mixing at about 60 revolutions (5 minutes at 12 rpm).

The tablets were compacted using a single station compressor (Korsch XP 1 or equivalent).

Example 7 Spray dried dispersion lozenge

Tablets were formed from the SDD of Example 5 using the following procedure. Add half the amount of microcrystalline cellulose to the blender (box blender or equivalent) And mixing at low speed for about 25 revolutions (2 minutes at 12 rpm). The SDD was added to the blender and the blender was rinsed and mixed with a portion of sodium chloride. A batch amount of succinic acid, sodium chloride, croscarmellose sodium, and colloidal cerium oxide was added and mixed at about 180 rpm (for 15 minutes at 12 rpm) at low speed. The final composition of the blend is given in Table 8.

The attritor and bag were precoated with microcrystalline cellulose in an amount of 25% by weight. The blend from the above procedure was passed through a grinder equipped with a 1601 impeller, a 018R mesh, and a 1000 speed Comil U5. The attritor is rinsed with the remaining batch portion of microcrystalline cellulose, and the ground material is transferred from the bag to a blender (box blender or equivalent) and at about 180 revolutions at low speed ( Mix at 12 rpm for 15 minutes).

The intragranular magnesium stearate is sieved through a suitable grading sieve and added first The blender of the previous step was then mixed at about 60 revolutions (5 minutes at 12 rpm) at low speed.

The blend was compacted using Korsch XP 1 or equivalent.

The compacted blend was passed through a grinder equipped with a 1601 impeller, a 050 G mesh and a speed of 1000 Comil U5. The amount of extragranular magnesium stearate required is calculated, sieved through a suitable grading sieve and added to the blender of the previous step. The mixture was then mixed over about 60 revolutions (for 12 minutes at 12 rpm).

The tablets were compacted using a single station compressor (Korsch XP 1 or equivalent).

Example 8 Dissolution test at pH 5.5

Preparation of a test lozenge formulation for dissolution testing comprising free base form of Pabsiri (API), water soluble acid, microcrystalline cellulose (Avicel PH 102), lactose monohydrate (Fast Flo 316), cross-linking Povidone (Kollidon CL) and magnesium stearate. The test tablet was prepared using the dry granulation (DG) method described in Example 1 with the following acids: malic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, toluenesulfonic acid, benzoic acid And benzenesulfonic acid. A test lozenge of malic acid and citric acid was prepared via direct compression (DC) (not dry granulation).

The tablets were subjected to a dissolution test in a USP 2 rotating apparatus having blades of spin at 50 rpm in 500 ml of 10 mM sodium acetate buffer pH 5.5 and at a temperature of 37 °C. Collect 6 ml samples at each pull point and pass Over 10 micron full flow filter. Off-line analysis was performed at a UV wavelength of 367 nm.

The comparative dissolution data was generated using the dry granulation method of Example 1 using a Pabsiodonium isethionate (ISE) capsule prepared from a blend lacking a water-soluble acid and a free base API tablet. The results of a dissolution test of a tablet containing succinic acid, maleic acid, malic acid, fumaric acid, and tartaric acid are shown in Fig. 1. Tablets containing succinic acid, malic acid, and tartaric acid exhibited superior solubility properties with greater than 50% drug dissolution at 30 minutes, as shown in FIG.

Example 9 Chemical stability of the formulation

The test tablet prepared in Example 8 was stored at 70 ° C / 75% RH for 8 days. The tablet was crushed and analyzed for impurities using the following high performance liquid chromatography (HLPC) method: Waters CSH C18, 2.1 x 100 mm, 1.7 micron column; mobile phase (gradient elution) A: 0.03% three Fluoroacetic acid, and B: 0.03% trifluoroacetic acid in acetonitrile; column temperature at 45 ° C; flow rate of 0.5 ml / min; UV detection at 234 nm; injection volume of 2 μl; and operation of 10.72 minutes time. The results are summarized in Table 9.

Tablets containing malic acid, succinic acid, benzoic acid, toluenesulfonic acid, tartaric acid, and benzenesulfonic acid have acceptable total impurities after storage for 8 days at 70 ° C / 75% RH. Formulations containing succinic acid, malic acid, and tartaric acid were further developed based on superior dissolution and stability experiments.

Example 10 Non-sink dissolution test 2

Development of a non-leaky in-tube dissolution method for screening formulations. In this method, the tablet was placed in a USP 2 (blade) device stirred at 50 rpm and in a solution of 500 ml of 50 mM phosphate buffer + 0.1 M NaCl (pH 6.5) at a temperature of 37 °C. Samples were collected periodically and filtered through a 10 micron filter. The API concentration was measured offline under UV of 367 nm. Example 1 (FB+ succinic acid, lozenge), Example 2 (FB+ succinic acid, bilayer tablet), Example 4 (FB+ succinic acid, FBG lozenge), Example 6 (SDD, lozenge) and The tablets prepared in Example 7 (SDD + succinic acid, lozenges) produced solvent data. The dissolution profile is shown in Figure 3. Dissolution data for commercially available Pabsiri free base capsules (free base capsules) with the formulation of Table 10 are also shown:

As shown in Fig. 3, the dosage forms of Examples 1, 2 and 4 which are subjected to the non-leakage dissolution conditions are (a) not less than 40% of Pabori in 15 minutes; (b) not within 30 minutes. Less than 35% of Pabsiri; (c) not less than 25% of Pabori in 60 minutes; or (d) two or more of (a), (b) and (c).

Example 11 Drug exposure of commercially available free base capsules

Random, single-dose, open-label, 4-sequence, and 4-phase crossover studies were performed in healthy volunteers. Twenty-eight (28) subjects under 4 different conditions or treatments (overnight fast [A], pre-dose high-fat diet [B], pre-dose low-fat diet [C] and before dosing 1 Hours and 2 hours after dosing The medium fat diet [D]) each received a single dose of 125 mg of Pabsiri.

The treatment sequences used in the first to fourth phases are shown in Table 11. There is at least a 10 day washout period between study periods. Subjects were allowed to undergo 144 hours of PK sampling after treatment administration. The pharmacokinetic parameter values are given in Table 12.

When the 125 mg Pabsiri commercially available capsule formulation was administered under fasting conditions, it exhibited lower AUC and Cmax than the exposure under three eating conditions. Therefore, it is recommended that commercially available capsules be administered together with food.

Example 12 Effect of antacids on bioavailability of pabexili

The aim of this study was to investigate the increase in gastric pH achieved by treatment with multiple doses of proton pump inhibitors (PPI, especially rabeprazole) for the administration of 125 mg of a single oral paclicil capsule under fasting conditions. Possible effects of kinetics (PK).

The results are summarized in Table 13 below. The 125 mg Pabsiri commercially available capsule formulation exhibited significantly lower AUC and Cmax than the separately administered paabutir when administered in the presence of rabeprazole.

Example 13 Effect of antacids on bioavailability of test formulations

Cross-over, open-label, non-random pharmacokinetic studies were performed in healthy volunteers to evaluate 125 mg of lozenges (single dose) of six experimental formulations of paclitaxel treated with antacids under fasting conditions in Rebecca Effect of the bioavailability of Pabsiri administered separately in the presence of latazole should. Tables 14(A)-(F) show the results of the 1-6 groups: Example 1, Example 6, Example 7, Example 2, Example 4, and 125 mg of Pabsiri oral solution.

Example 14 Accelerated stability test

The tablet of Example 1 (anhydrous granule + succinic acid) was subjected to accelerated stability using the following conditions. The tablets were placed in a beaker under the conditions shown below. Humidity control is achieved by oven control or saturated salt solution. Samples were removed periodically from the conditions shown in Table 15 below. Samples (including unexposed controls) were stored in the refrigerator until analysis.

The specified relative humidity was maintained with the following saturated salts: 22% RH via potassium acetate; 50% RH at 30 °C and 40 °C via sodium bromide; and 75% RH via a humidity controlled oven.

The degradant is an amber oxime-based adduct of API having the following structure:

The samples were prepared as follows: Each tablet was added to a 100 ml volumetric flask, and a stir bar and 100 ml of dissolved solvent (1440 ml of water: 400 ml of acetonitrile: 160 ml of 1 N HCl; 80:20 of 0.1 N HCl: acetonitrile) were added. The flask was placed on a stir plate and the sample was stirred for 1 hour at the highest available agitation speed. The aliquot was then removed and centrifuged at 3000 RPM for 5 minutes in a polypropylene tube. The supernatant was diluted 1 :5 with dissolved solvent and sampled into an HPLC vial for analysis. Each tablet at a final solution concentration of 0.25 mg/ml contained 125 mg of API. The samples were analyzed using the following HPLC methods. The results are presented in Table 15 below and show excellent long term stability.

Dissolving solvent (diluent): 1440 ml water: 400 ml acetonitrile: 160 ml 1 N HCl / / / (80: 20 0.1 N HCl: acetonitrile)

Mobile phase:

Mobile phase A: 0.03% trifluoroacetic acid (0.6 ml trifluoroacetic acid in 2000 ml water)

Mobile phase B: 0.03% trifluoroacetic acid in acetonitrile (in 2000 ml) 0.6 ml of trifluoroacetic acid in acetonitrile) 0.5 ml / min

gradient

234 nm, area % relative to Pabsiri (main peak) 2 μl sample injection (prepared as indicated below). The sample chamber is maintained at 5 ° C

Sample Preparation

The samples were prepared as follows: Each tablet was added to a 100 ml volumetric flask, and a stir bar and 100 ml of dissolution solvent were added. The flask was placed on a stir plate and the sample was stirred for 1 hour at the highest available agitation speed. The aliquot was then removed and centrifuged at 3000 RPM for 5 minutes in a polypropylene tube. The supernatant was diluted 1 :5 with dissolved solvent and sampled into an HPLC vial for analysis. Each tablet at a final solution concentration of 0.25 mg/ml contained 125 mg of API.

Further, the tablet (fluid bed granule + succinic acid) of Example 4 was analyzed in the same manner. The results are presented in Table 16 below and show the concentration of degradants that are unacceptable for long term stability.

Example 15 Long-term storage stability

The tablet and desiccant cartridge of Example 1 were packaged in a bottle using a heat sensitive seal. After storage for 1 year at 25 ° C / 60% RH, the tablet has less than 0.05% amber thiol addition. The tablet and desiccant cartridge of Example 4 were packaged in a HDPE bottle using a heat sensitive seal. After 6 months storage at 25 ° C / 60% RH, the tablet has an amount of amber oxime addition of less than 0.23%.

Example 16 Coated lozenge formulation

Table 17 illustrates the optimization of formulations A1, A2, and B, which show that the solid dosage form is commercially acceptable for manufacturing performance. Tablets were formed using the following procedure. Microcrystalline cellulose PH102, colloidal cerium oxide, intragranular cross-linked povidone CL and API were blended together and homogenized by Comil. The intragranular magnesium stearate is blended therein. The mixture was dry granulated using roller compaction and particle milling.

The sieved succinic acid, microcrystalline cellulose PH-200, and granule diplomatic ketoxime (CL or CL-SF grade) are blended into the granules. The extragranular magnesium stearate or sodium stearyl fumarate as a tableting lubricant is mixed into the final blend. A tablet is formed using a rotary tablet press having a pre-compression. Formulation A2 uses an external lubrication system (ELS) to apply the lubricant directly to the tablet punch at a nominal amount.

The tablets were coated with a solids content of 12% w/w Opadry Pink (03K140024) and purified water to a 2 to 4% weight gain.

Example 17 Optimized lubricant content

Formulations were prepared in different amounts of intragranular and extragranular magnesium stearate lubricant as described for use in Formulation A2 in Example 16, as shown in Table 17. The hardness of each formulation (slurry breaking force, USP<1217>), brittleness (USP<1216>100 rpm), stretch brittleness (USP<1216>375 rpm) and punch adhesion were measured (Hutchins, MacDonald, Mullarney, Assessing Tablet-Sticking Propensity, Pharmaceutical Technology, Volume 36, Issue 1, 2012), as described in Table 18. The reduced sample size was used in the USP method.

Reducing the amount of intragranular and extragranular lubricant significantly increases tablet hardness and reduces brittleness. Lozenge adhesion is more sensitive to the amount of extragranular lubricant than to the amount of lubricant in the granule. The adhesion is significantly reduced by increasing the extragranular magnesium stearate content. No difference in knurling/smoothing roll adhesion was observed with different intragranular magnesium stearate content. As shown in Table 18, the amount of intragranular/extragranular lubricant dispensed from 1% by weight/0% by weight to 0.33% by weight/0.5% by weight provides good tablet strength, reduced brittleness and reduced formulation. Adhesion of the A2 tablet. A lubricant content of about 5% by weight of sodium stearyl fumarate or 2% by weight of fine-grained stearate (CaSt 2249) reduces punch adhesion and tablet defects.

Example 18 Optimized tablet hardness and brittleness

Formulations were prepared as outlined in Example 16 for Formulation 12, changing the order of addition of acid, addition of lactose monohydrate, addition of anhydrous binder (Kollidon SF, Avicel PH105, Klucel EXF) and modification of intragranular crystallites. The ratio of cellulose to extragranular microcrystalline cellulose. The properties of the different formulations were measured: initial blend loading density (USP <616>), roll compacted tensile strength (Zinchuk AV, Mullarney MP, Hancock BC. Simulation of roller compaction using a Laboratory scale compaction simulator. Int J Pharm. 2004 Jan 28; 269(2): 403-15.), punch adhesion (Hutchins, MacDonald, Mullarney, Assessing Tablet-Sticking Propensity, Pharmaceutical Technology, Volume 36, Issue 1, 2012), tablet hardness (slurry breaking force, USP<1217>), fragility (USP<1216> via 375 rpm) and disintegration time (USP<701>). The reduced sample size was used in the USP method.

Formulations without lactose showed higher tablet hardness and lower brittleness. In addition, the addition of SF (ultrafine particle) grade Kollidon helps to reduce the disintegration time while increasing the tablet hardness. It has been found that the addition of an acid outside the particles is preferred to achieve a shorter disintegration time.

Self-formulation removal of lactic acid provides a lozenge with reduced fragility that still maintains rapid disintegration. The inclusion of a water-free binder does not provide the added benefit of reducing brittleness, but slightly reduces adhesion. However, the inclusion of a binder may have a negative impact on disintegration/expansion in some cases.

Example 19 In-vitro dissolution of formulations A1, A2 and B

The in-tube dissolution of the optimized formulations A1, A2 and B was determined using Dissolution Test 2 in the non-leaky state (pH 6.5, 50 mM phosphate buffer, 0.1 M NaCl) described in Example 10. The dissolution profile of the formulations was compared to the tablets prepared according to Examples 1 to 7. The lozenge of Example 1 showed no drug-drug interaction with the proton pump inhibitor in the fasting state of the human volunteer and was set to the minimum target dissolution profile. The comparative dissolution data is presented in Figure 4. Formulations A1, A2, and B were all superior to commercially available free base capsules (as described in Example 10) and were used in early development to have the formulation of Table 20, Pabburi hydroxyethyl sulfonate. Both acid salt (ISE) capsules. After 10 minutes, the formulations A1, A2 and B were all superior to the tablets of Examples 1 to 7, and thus conformed to the solid dosage form dissolution target.

Example 20 Impact of succinic acid particle size distribution

According to the acid received (large particle size distribution of up to 1 mm diameter) and acid Three sieve cuts were used to determine the impact of the succinic acid particle size distribution on the amber-based adduct formation rate. The smaller the acid particle size results in a larger impurity formation rate because its larger specific surface area allows the acid to contact the free base API more frequently. Therefore, acids having a particle size greater than about 100 microns are preferred in pharmaceutical product formulation to improve chemical stability.

Example 21 Physical stability analysis

Quantitative Raman spectroscopy was developed to assess the physical stability of the formulation. The Raman method uses the Kaiser Optical Systems PhAT probe and the quantitative mode is established using a set of calibration standards prepared from API, API succinate complexes and excipients. The relative stability of formulations A1 and B was assessed by measuring the amount of API succinate complex in the formulation after storage of the tablet at 30 to 50 ° C and up to 75% RH for up to 1 month.

Formulation B showed a lower succinate complex conversion relative to formulation A1. The conversion amount increases with time and is accelerated by storage conditions of higher temperature and humidity.

The amount of API succinate complex formed by formulations A1 and B under various temperature and humidity conditions is shown in Table 22 as a function of time, where 〝LOD〞 refers to the limit of detection and the specified amount of 〝LOQ 〞.

The physical stability of the uncoated prototype tablet formulation A1 under open conditions was evaluated. The temperature and humidity at which the tablet is raised. Conversion of the succinate complex was observed in stressed samples using Raman spectroscopy.

The chemical purity of Formulations A1 and B after storage for 1 month at 40 ° C / 75% RH was compared. As shown in Table 23, Formulation B showed a significantly lower total impurity formation relative to Formulation A1.

Determination of humidity (%RH) based on these data has a significant impact on the API conversion rate from the free base to the succinate complex. Increasing the temperature also impacts the conversion of the composite, but has a weaker effect than the humidity.

Tablets pre-equilibrated in 60% RH prior to metal foil-foil-foil packaging exhibited rapid succinate complex formation. The stability data for Week 9 indicated the need to control the water activity in the tablet to minimize the formation of the Pabsiri succinate complex in the drug product. Formulation B (which contains extragranular stearyl fumarate as a lubricant) shows lower than the formulation A1 (which incorporates magnesium stearate as an extragranular lubricant) under high humidity (75% RH) conditions. Succinate complex conversion.

Claims (20)

A solid dosage form comprising from about 10% to about 35% by weight of Pabsiri, from about 5% to about 25% by weight of a water-soluble acid selected from the group consisting of succinic acid, malic acid and tartaric acid And a pharmaceutically acceptable carrier. A solid dosage form according to claim 1 wherein the water soluble acid is succinic acid. The solid dosage form according to claim 1 or 2, wherein the pharmaceutically acceptable carrier comprises at least one diluent, and wherein the diluent constitutes from about 50% to about 75% by weight of the solid dosage form. The solid dosage form according to claim 3, wherein the diluent is selected from the group consisting of microcrystalline cellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesium carbonate, hydrogen phosphate Dibasic calcium phosphate and tribasic calcium phosphate. The solid dosage form of claim 1, wherein the pharmaceutically acceptable carrier comprises at least one lubricant, and wherein the lubricant comprises from about 0.5% to about 10% by weight of the solid dosage form. A solid dosage form according to claim 5, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate and sodium stearyl fumarate. The solid dosage form of claim 1, wherein the pharmaceutically acceptable carrier comprises at least one disintegrant, and wherein the disintegrant comprises from about 5% to about 10% by weight of the solid dosage form. A solid dosage form according to claim 7 wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium and glycolic acid. Sodium starch glycolate. The solid dosage form according to item 1 of the patent application is in the form of a tablet. A solid dosage form according to claim 9 wherein the tablet is coated. A solid dosage form according to claim 9 wherein the tablet is a bilayer tablet. The solid dosage form according to claim 2, wherein the dosage form is added to a test medium comprising 500 ml of 10 mM acetate buffer of pH 5.5 at 37 ° C in a standard USP 2 rotary vane apparatus having blades with spins at 50 rpm. In the middle, it dissolves: (a) not less than 35% of Pabori in 15 minutes; (b) not less than 45% of Pabori in 30 minutes; (c) not less than 60 minutes in 60 minutes 55% of Pabbori; or (d) two or more of (a), (b) and (c). The solid dosage form according to claim 2, wherein the dosage form is added to a standard USP 2 rotary vane device having a blade having a spin of 50 rpm, comprising 500 ml of 50 mM phosphate buffer pH 6.5 at 37 ° C and 0.1 M In the test medium of NaCl, it dissolves: (a) not less than 40% of Pabori in 15 minutes; (b) less than 35% of Pabori in 30 minutes; (c) in 60 minutes Not less than 25% of Pabori; or (d) two or more of (a), (b) and (c) By. The solid dosage form according to item 2 of the scope of the patent application, wherein the dosage form: (a) has an average area (AUC) of from about 0.8 to about 1.25 in a plasma concentration versus time curve after administration of a single oral dose to the subject. / fasting ratio; (b) an average eating/fasting ratio having a maximum plasma concentration ( _Cmax ) from about 0.8 to about 1.25 after administration of a single oral dose to the subject; or (c) (a) and (b) )both. A solid dosage form according to item 2 of the scope of the patent application, wherein the dosage form: (a) provides a controlled immediate release (IR) oral capsule containing an equivalent amount of Pabsiri after administration of a single oral dose to the subject Average fasting AUC within the range of 80% to 125% of the average fasting AUC; (b) providing an immediate release type (IR) containing an equivalent amount of Pabsiri after administration of a single oral dose to the subject the mean 80-125% of the opening of the capsule fasting average of the range of fasting plasma C _max C _max; or (c) (a) and both (b). A solid dosage form according to claim 2, wherein the dosage form provides: (a) an average AUC line in the presence of a proton pump inhibitor (PPI) after administration of a single oral dose to the subject in the absence of PPI in the range of 80-125% of the mean AUC; (b) at a mean C _max based proton pump inhibitor (PPI) is present in the subject after a single oral administration dose mean C _max occurring in the absence of PPI 80% to 125% of the range; or (c) both (a) and (b). A solid dosage form according to claim 16 wherein the PPI is rabeprazole. A solid dosage form according to claim 2, wherein the dosage form exhibits less than 0.05% by weight acid adduct after storage for one year at 25 ° C and 60% RH. A solid dosage form according to item 2 of the scope of the patent application, wherein the amount of paclitaxel in the dosage form is 25 mg, 75 mg, 100 mg or 125 mg. A solid dosage form according to claim 19, wherein the amount of Pabbori in the dosage form is 125 mg.